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EP0438147A2 - Compositions pharmaceutiques et formes de dose pour l'administration orale de la calcitonine - Google Patents

Compositions pharmaceutiques et formes de dose pour l'administration orale de la calcitonine Download PDF

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Publication number
EP0438147A2
EP0438147A2 EP91100509A EP91100509A EP0438147A2 EP 0438147 A2 EP0438147 A2 EP 0438147A2 EP 91100509 A EP91100509 A EP 91100509A EP 91100509 A EP91100509 A EP 91100509A EP 0438147 A2 EP0438147 A2 EP 0438147A2
Authority
EP
European Patent Office
Prior art keywords
calcitonin
pharmaceutical composition
tablets
oral administration
active principle
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91100509A
Other languages
German (de)
English (en)
Other versions
EP0438147A3 (en
Inventor
Filippo Lattanzi
Maurizio Cecchettin
Riccardo Vanni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sclavo SpA
Original Assignee
Sclavo SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sclavo SpA filed Critical Sclavo SpA
Publication of EP0438147A2 publication Critical patent/EP0438147A2/fr
Publication of EP0438147A3 publication Critical patent/EP0438147A3/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • This invention relates to pharmaceutical compositions containing a calcitonin as active principle, homogenized with a mixture of solid excipients suitable for oral administration in the form of tablets.
  • the present invention relates to sublingual and perbuccal tablets suitable for the oral administration of a calcitonin, obtained using said pharmaceutical compositions.
  • calcitonins constitute a known class of pharmacologically active long-chain polypeptides the use of which has been well described in the literature.
  • Various calcitonins including for example salmon and eel calcitonin, are currently used for treating for example Paget's disease, Sudek's disease and osteoporosis.
  • nasal clinical treatment using a nasal spray results in very low absorption of the active principle, even if high doses are used. Specifically, using doses four times greater than those used for parenteral administration, an absorption of 30% is obtained.
  • the object of the present invention is consequently to find other calcitonin administration means which overcome the drawbacks of the known art.
  • hematic calcitonin levels equivalent to those obtained by intramuscular administration in the usual doses can be obtained by oral administration of a calcitonin in the form of perbuccal or sublingual tablets in doses which fall within the limits of tolerability and practicality.
  • Oral administration is a simple and painless method which can be easily used by the patient himself, employing perbuccal or sublingual tablets.
  • a pharmaceutical composition for oral application in the form of sublingual and perbuccal tablets must be well tolerated, particularly at the site of its application, must not irritate the mucosa, and must not result in a too rapid disintegration of the tablet in the case of perbuccal tablets, which disintegration furthermore must be incomplete or absent in the case of sublingual tablets.
  • Bioavailability can be defined as the quantity of medicament absorbed into the blood from an administered pharmaceutical product.
  • the bioavailability of a pharmacologically active compound depends on numerous factors, such as the excipients used for preparing the pharmaceutical compositions, the technology used for preparing the dosage forms and the physico-chemical properties of the active principle.
  • two products of the same type (tablets) containing the same quantity of the same active ingredient can show different degrees of bioavailability, ie they are chemically equivalent but not necessarily bioequivalent.
  • two chemically identical products to be bioequivalent must attain the same plasmatic concentration within the same time.
  • the present invention therefore provides pharmaceutical compositions containing a calcitonin as active principle and suitable for oral administration in the form of perbuccal and sublingual tablets in which said calcitonin is homogenized with a mixture of solid excipients, said excipients consisting of a diluent, a lubricant, a disintegrating agent in the case of sublingual tablets, and a binder in the case of perbuccal tablets.
  • the invention also provides unit dosage forms for the oral administration of a calcitonin in the form of perbuccal and sublingual tablets, prepared using said compositions.
  • compositions of the present invention consist of a homogenate of the active principle, possibly mixed with a suitable stabilizer, with a mixture of solid ingredients, said mixture consisting of:
  • the active principle for use in the formulations of the present invention can be chosen from calcitonins of natural or synthetic origin such as salmon calcitonin (SCT), eel calcitonin (ECT) or pig calcitonin, or synthetic analogues such as (Asu 1,7 )ECT commonly known as carbocalcitonin.
  • SCT salmon calcitonin
  • ECT eel calcitonin
  • pig calcitonin eel calcitonin
  • synthetic analogues such as (Asu 1,7 )ECT commonly known as carbocalcitonin.
  • the quantity of active ingredient to be used in the composition depends on the type of calcitonin used, the disease to be treated, the desired frequency of administration and the desired effect. Generally, active principle quantities of between 20 and 800 I.U. and preferably between 50 and 500 I.U. per tablet (100-150 g) are used.
  • Diluents suitable for the purposes of the present invention can be chosen from mannitol, lactose, saccharose or a mixture of lactose and saccharose in a quantity of between 20 and 70% and preferably between 30 and 55% by weight with respect to the total weight of the tablet.
  • Disintegrating agents suitable for the purposes of the present invention are chosen from starch, sodiumcarboxymethyl starch, carboxymethylcellulose, microcrystalline cellulose, crospovidone, amberlite and alginic acid in a quantity of between 1 and 15%, and preferably 5-10% in the case of microcrystalline cellulose and 1-3% in the case of the other disintegrating agents, by weight with respect to the total weight of the tablet.
  • Binders able to delay solubilization of the perbuccal tablet are chosen generally from gum arabic and cellulose derivatives such as hydroxypropylcellulose and hydroxypropylmethylcellulose in a quantity of between 1 and 25% and preferably between 5 and 10% by weight with respect to the total weight of the tablet.
  • Lubricants are chosen from magnesium stearate, aluminium stearate, stearic acid, high molecular weight PEG or talc, in a concentration of between 0.3 and 5% and preferably between 0.5 and 2%.
  • compositions for the preparation of sublingual and perbuccal tablets can also contain colouring and flavouring agents.
  • compositions according to the present invention are well tolerated and do not induce undesirable side effects.
  • compositions described in Examples 1 and 2 for the preparation of sublingual tablets are distinguished by a bioavailability with in the first case peaks of lesser but constant intensity (150-160 pg/ml), and in the second case a peak of greater intensity (200-210 pg/ml) and a more rapid decline, but which remains at a good level ( Figures 1 and 2).
  • compositions of the present invention and in particular of this method of administration is the surprising uniformity of the results and hence of the bioavailability of the active principle.
  • the absorption of the active principle which is practically immediate and less sensitive to variables, is between 70% and 90%.
  • the tablets can be prepared by directly compressing the pulverized or granulated mixture of the active principle and excipients using currently available equipment for this purpose.
  • Sublingual tablets weighing approximately 100 mg were prepared having the following composition:
  • Blood samples were taken at time 0 and at 5, 10, 60, 90 and 120 minutes after administration.
  • the calcitonin concentration in the serum was determined by radio-immunological assay.
  • Sublingual tablets weighing approximately 100 mg were prepared having the following composition: where ludipress is lactose plus polyvinylpyrrolidone (PVP).
  • ludipress is lactose plus polyvinylpyrrolidone (PVP).
  • Blood samples were taken at time 0 and at 5, 10, 20, 30, 60, 90 and 120 minutes after administration.
  • the calcitonin concentration in the serum was determined by radio-immunological assay.
  • the quantities indicated represent a formulation usable for preparing 1000 tablets each weighing about 100 mg.
  • Perbuccal tablets weighing about 150 mg were prepared having the following composition:
  • Blood samples were taken at time 0 and at 15, 30, 60 and 120 minutes after administration.
  • the calcitonin concentration in the serum was determined by radio-immunological assay.
  • the quantities indicated represent a formulation usable for preparing 1000 tablets each weighing about 150 mg.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physiology (AREA)
  • Nutrition Science (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP19910100509 1990-01-19 1991-01-17 Pharmaceutical compositions and dosage forms for the oral administration of calcitonin Withdrawn EP0438147A3 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT01911290A IT1238072B (it) 1990-01-19 1990-01-19 Composizioni farmaceutiche e forme di dosaggio per la somministrazione orale di calcitonina
IT1911290 1990-01-19

Publications (2)

Publication Number Publication Date
EP0438147A2 true EP0438147A2 (fr) 1991-07-24
EP0438147A3 EP0438147A3 (en) 1991-10-16

Family

ID=11154741

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910100509 Withdrawn EP0438147A3 (en) 1990-01-19 1991-01-17 Pharmaceutical compositions and dosage forms for the oral administration of calcitonin

Country Status (7)

Country Link
US (1) US5441933A (fr)
EP (1) EP0438147A3 (fr)
JP (1) JPH04210924A (fr)
KR (1) KR910014128A (fr)
CA (1) CA2034519A1 (fr)
IT (1) IT1238072B (fr)
MX (1) MX24039A (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0535827A1 (fr) * 1991-09-28 1993-04-07 Ciba-Geigy Ag Suspensions à base de calcitonine pour l'administration orale
US5958453A (en) * 1996-10-31 1999-09-28 Takeda Chemical Industries, Ltd. Solid pharmaceutical preparation with improved buccal disintegrability and/or dissolubility
WO2001070194A1 (fr) * 2000-03-23 2001-09-27 Warner-Lambert Company Films consommables par voie orale a dissolution rapide contenant une resine d'echange ionique comme agent de masquage du gout
ES2199061A1 (es) * 2002-06-10 2004-02-01 Vita Lab Comprimidos bucodispersables y procedimiento para su obtencion.
WO2005065640A1 (fr) * 2004-01-06 2005-07-21 Panacea Biotec Ltd. Nouvelles compositions pour formes posologiques orales, et procede de preparation de telles compositions
US7049283B2 (en) 2000-12-06 2006-05-23 Novartis Ag Pharmaceutical compositions for the oral delivery of pharmacologically active agents
US7070805B2 (en) 1998-07-28 2006-07-04 Takeda Pharmaceutical Company Limited Rapidly disintegrable solid preparation
US7431942B2 (en) 1998-05-18 2008-10-07 Takeda Pharmaceutical Company Limited Orally disintegrable tablets

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU776299B2 (en) * 1998-12-01 2004-09-02 Dr Reddy's Laboratories, Inc. New pharmaceutical composition and the process for its preparation
US20040265372A1 (en) * 2003-06-27 2004-12-30 David Wynn Soft tablet containing high molecular weight cellulosics
EP1781257B1 (fr) * 2004-08-13 2018-12-19 Emisphere Technologies, Inc. Formulations pharmaceutiques contenant des microparticules ou des nanoparticules d'un agent d'administration
US8197858B2 (en) * 2009-02-06 2012-06-12 Mark John Zamoyski Bone microenvironment modulated seizure treatments
US9486947B2 (en) * 2013-09-30 2016-11-08 Gregory D. Graves Phosphorus treatment agent methods of manufacture and use

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4151276A (en) * 1975-05-12 1979-04-24 Armour Pharmaceutical Company Method of suppressing gastric acid secretion by the oral administration of calcitonin
US4663309A (en) * 1983-06-29 1987-05-05 University Patents, Inc. Novel peptide hormones with calcitonin-like activity
US4530838A (en) * 1983-07-08 1985-07-23 The Salk Institute For Biological Studies Synthetic calcitonin-gene-related peptides for lowering blood pressure or gastric acid secretion in mammals
JPS61126034A (ja) * 1984-11-26 1986-06-13 Yamanouchi Pharmaceut Co Ltd アルド−スを含有するカルシトニン経鼻剤
US5288497A (en) * 1985-05-01 1994-02-22 The University Of Utah Compositions of oral dissolvable medicaments
JPS6210020A (ja) * 1985-07-08 1987-01-19 Kanebo Ltd カルシトニン含有組成物
IT1223132B (it) * 1987-11-13 1990-09-12 Isf Spa Composizione farmaceutica per somministrazione nasale
DE3887494T2 (de) * 1987-11-13 1994-05-19 Smithkline Beecham Farma Ein Calcitonin sowie ein Glycyrrhizinat als Absorptionsförderer enthaltende Arzneimittel.

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0535827A1 (fr) * 1991-09-28 1993-04-07 Ciba-Geigy Ag Suspensions à base de calcitonine pour l'administration orale
US5958453A (en) * 1996-10-31 1999-09-28 Takeda Chemical Industries, Ltd. Solid pharmaceutical preparation with improved buccal disintegrability and/or dissolubility
US6248357B1 (en) 1996-10-31 2001-06-19 Takeda Chemical Industries, Ltd. Solid pharmaceutical preparation with improved buccal disintegrability and/or dissolubility
US9901546B2 (en) 1998-05-18 2018-02-27 Takeda Pharmaceutical Company Limited Orally disintegrable tablets
US7875292B2 (en) 1998-05-18 2011-01-25 Takeda Pharmaceutical Company Limited Orally disintegrable tablets
US7431942B2 (en) 1998-05-18 2008-10-07 Takeda Pharmaceutical Company Limited Orally disintegrable tablets
US7070805B2 (en) 1998-07-28 2006-07-04 Takeda Pharmaceutical Company Limited Rapidly disintegrable solid preparation
EP1674078A3 (fr) * 2000-03-23 2007-07-25 Warner-Lambert Company LLC Films consommables par voie orale à dissolution rapide contenant une résine d'échange ionique comme agent de masquage du goût
US7067116B1 (en) 2000-03-23 2006-06-27 Warner-Lambert Company Llc Fast dissolving orally consumable solid film containing a taste masking agent and pharmaceutically active agent at weight ratio of 1:3 to 3:1
US7648712B2 (en) 2000-03-23 2010-01-19 Mcneil-Ppc, Inc. Fast dissolving orally consumable films containing a taste masking agent
WO2001070194A1 (fr) * 2000-03-23 2001-09-27 Warner-Lambert Company Films consommables par voie orale a dissolution rapide contenant une resine d'echange ionique comme agent de masquage du gout
US7049283B2 (en) 2000-12-06 2006-05-23 Novartis Ag Pharmaceutical compositions for the oral delivery of pharmacologically active agents
ES2199061A1 (es) * 2002-06-10 2004-02-01 Vita Lab Comprimidos bucodispersables y procedimiento para su obtencion.
WO2005065640A1 (fr) * 2004-01-06 2005-07-21 Panacea Biotec Ltd. Nouvelles compositions pour formes posologiques orales, et procede de preparation de telles compositions

Also Published As

Publication number Publication date
IT9019112A0 (it) 1990-01-19
IT1238072B (it) 1993-07-03
KR910014128A (ko) 1991-08-31
IT9019112A1 (it) 1991-07-19
EP0438147A3 (en) 1991-10-16
JPH04210924A (ja) 1992-08-03
US5441933A (en) 1995-08-15
MX24039A (es) 1994-02-28
CA2034519A1 (fr) 1991-07-20

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